Substituted aminophenylsulfonamide compounds as HIV protease inhibitor

Abstract

The present invention concerns substituted aminophenylsulfonamide compounds, their use as protease inhibitors, in particular as broad-spectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. The present invention also concerns combinations of the present substituted aminophenylsulfonamide compounds with another anti-retroviral agent. It further relates to their use in assays as reference compounds or as reagents.

1. A compound having the formula 
       
         
           
           
               
               
           
         
       
       or N-oxide, salt, stereoisomeric form, racemic mixture, or ester thereof wherein
 R 1  and R 2  are, each independently, hydrogen, C 1-6 -alkyl preferably C 1-4 -alkyl optionally substituted by C 1-6 alkyloxy, hydroxyl, C 3-7 cycloalkyl, aryl, benzodioxolyl, Het 1 , Het 2  or X wherein; 
 X is a carbon or nitrogen optionally substituted by —C(═O)—NH 2 , C 1-6 alkyloxy-C(═O)— or C 1-6 alkyl-C(═O)—, 
 Aryl as a group or part of a group is meant to include phenyl which may be optionally substituted with one or more substituents independently selected from C 1-6 alkyl, C 1-6 alkyloxy, aminoC 1-6 alkyl, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloC 1-6 alkyl, carboxyl, C 1-6 alkoxycarbonyl, C 3-7 cycloalkyl, Het 1 , Het 2  optionally mono- or disubstituted aminocarbonyl, methylenedioxy, methylthio or methylsulfonyl, 
 Het 1  as a group or part of a group is defined as a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 14 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulphur and which is optionally substituted on one or more nitrogen and/or carbon atoms by C 1-6 alkyl, C 1-6 alkyloxy, aminoC 1-6 alkyl, halogen, hydroxy, acetyl, oxo, optionally mono- or disubstituted amino, optionally mono- or disubstituted aminoalkyl, nitro, cyano, haloC 1-6 alkyl, carboxyl, C 1-6 alkoxycarbonyl, C 3-7 cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic cycle or heterocycle having 3 to 14 ring members; and wherein 
 Het 2  as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 14 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulphur and which is optionally substituted on one or more nitrogen and/or carbon atoms by C 1-6 alkyl which may optionally substituted by C 3-7 cycloalkyl, C 1-6 alkyloxy, aminoC 1-6 alkyl, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloC 1-6 alkyl, carboxyl, C 1-6 alkoxycarbonyl, C 3-7 cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het 1  and an aromatic monocyclic, bicyclic or tricyclic cycle or heterocycle having 3 to 12 ring members. 
 
     
     
       2. A compound according  claim 1  wherein
 R 1  is hydrogen and 
 R 2  is C 1-6 -alkyl preferably C 1-4 -alkyl substituted by aryl which is substituted by halogen, or wherein said C 1-6 -alkyl preferably C 1-4 -alkyl is substituted by Het 2 , or wherein said C 1-6 -alkyl preferably C 1-4 -alkyl is substituted by benzodioxolyl. 
 
     
     
       3. A compound according to  claim 2  wherein
 R 1  is hydrogen and 
 R 2  is C 1-4 -alkyl substituted by aryl, which is di-substituted by fluoride, or wherein said C 1-4 -alkyl is substituted by a saturated monocyclic heterocycle having 6 ring members containing nitrogen. 
 
     
     
       4. A compound according to  claim 3  wherein the compound is (3-{[4-amino-3-(2,4-difluoro-benzylamino)-benzenesulfon-yl]-isobutyl-amino}-1-benzyl-2-hydroxy-propyl)carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester or [3-({4-amino-3-[(pyridin-2-ylmethyl)-amino]-benzenesulfonyl}-isobu-tyl-amino)-1-benzyl-2-hydroxy-propyl]carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester. 
     
     
       5. A pharmaceutical composition comprising an effective amount of at least one compound as claimed in  claim 1  and a pharmaceutically tolerable excipient. 
     
     
       6. A method of inhibiting a protease of a multi-drug resistant retrovirus in a mammal infected with said retrovirus comprising administering a protease-inhibiting amount of a compound according to  claim 1  to said mammal in need thereof. 
     
     
       7. A method of treating or combating infection or disease associated with multi-drug resistant retrovirus infection in a mammal comprising administering an effective amount of at least one compound according to  claim 1  to said mammal. 
     
     
       8. A method of inhibiting multi-drug resistant retroviral replication comprising contacting a retrovirus with an effective amount of at least one compound according to  claim 1 . 
     
     
       9. A composition comprising at least (a) a compound of formula (I) or (II) as claimed in  claim 1  and, (b) a second antiretroviral agent for the simultaneous, separate or sequential use.